Defining the Extrinsic Sensory Innervation of the Distal Gastrointestinal Tract

Abstract

Abdominal pain is a common symptom that greatly impacts patient quality of life and can be due to a variety of underlying gastrointestinal (GI) diseases. Sensory neurons that are intrinsic and extrinsic to the GI tract play a central role in mediating pain signals in response to various stimuli and yet little is known about their functional properties. My goal is to establish the functional role of the extrinsic innervation of the distal colon and to ultimately develop therapies to treat colonic pain. Here, I began to characterize the extrinsic innervation of the colon. I used mouse genetic tools that have previously been reported to be specific for dorsal root ganglia (DRG) sensory neurons but have not been well defined in the GI tract. I found that genetic tools employing the calcitonin gene-related peptide (CGRP-alpha) gene are specific for labeling the peptidergic DRG neuron extrinsic innervation of the GI tract, whereas Advillin or Phosphoinositide Interacting Regulator of Transient Receptor Potential Channels (Pirt) genetic labeling tools are not specific. I also established behavioral assays in the lab for colonic pain as well as an optogenetic approach to manipulate colon-innervating DRG neuron subtypes, and these are being used to study the functional properties of the CGRP-alpha+ colon innervating DRG neurons and their roles in pain associated with inflammation and distension of the colon. Thus, we begin to characterize the morphology and anatomy of the extrinsic sensory neurons with cell bodies within the DRG that innervate the distal colon, establishing the basis for the future study of sub-populations of these neurons. These studies will be crucial for understanding the perception of different etiologies of abdominal pain, including colitis, distension, and ischemia, and thus hopefully uncovering therapeutic targets.